EP0643974B1 - Impfstoff gegen die Lyme-Krankheit - Google Patents

Impfstoff gegen die Lyme-Krankheit Download PDF

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Publication number
EP0643974B1
EP0643974B1 EP94112143A EP94112143A EP0643974B1 EP 0643974 B1 EP0643974 B1 EP 0643974B1 EP 94112143 A EP94112143 A EP 94112143A EP 94112143 A EP94112143 A EP 94112143A EP 0643974 B1 EP0643974 B1 EP 0643974B1
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antigen
burgdorferi
ospa
recombinant
vector
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German (de)
English (en)
French (fr)
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EP0643974A1 (de
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Markus M. Dr. Simon
Ulrich E. Schaible
Klaus Prof. Dr. Eichmann
Michael Dr. Kramer
Wallich Dr. Reinhard
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Deutsches Krebsforschungszentrum DKFZ
Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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Deutsches Krebsforschungszentrum DKFZ
Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/20—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Spirochaetales (O), e.g. Treponema, Leptospira
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
    • C07K16/1207—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Spirochaetales (O), e.g. Treponema, Leptospira
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Lyme disease is the most common tick-borne disease Infectious disease in the temperate latitudes. It is caused by the spirochete Borrelia burgdorferi, which is mainly due to ticks of the tribe Ixodes is transferred to humans. The disease is one chronic progressive infection that many organs like the skin, the central and peripheral nervous system, the Heart, liver, kidney and musculoskeletal System affects. Because a reliable treatment of this Disease through antibiotic therapy is difficult great efforts are currently being made to Pathogen itself and the host's immune response to infection with B. burgdorferi.
  • the object underlying the invention is a to provide effective vaccine against Lyme disease.
  • a mouse strain be functional T and B cells, the so-called Scid mouse (Bosma et al., (1983) Nature 10, 52), serve as a test animal can, since Scid mice are infected with a pathogenic B. burgdorferi isolate is a multisystemic disease mainly polyarthritis and carditis, develop.
  • This animal model makes it possible the effect of vaccines against Lyme disease to try.
  • Subject of claim 1 for the contracting states ES and GR is a method for obtaining an antigen that is associated with a Antibodies against the 31 kD antigen (OspA) from B.burgdorferi ZS7 immunoreacts and the amino acid sequence shown in Fig. 1 or contains an immunogenic epitope from this sequence, whereby the coding DNA sequence for it into a host cell introduces, expresses the DNA sequence in the host cell and the antigen wins.
  • Subject of the claims 2 to 6 for the contracting states ES and GR are preferred Embodiments of this method.
  • Subject of claim 7 for the contracting states ES and GR is a procedure for Obtaining antigens from B.burgdorferi ZS7.
  • Subject of Claims 8 to 10 for the contracting states ES and GR is a Process for the preparation of an active vaccine against the Lyme disease, which has one or more antigens associated with one Antibodies against the 31kD antigen (OspA) from B.burgdorferi immunoreact or with an antibody against the 34 kD Immunizing B.burgdorferi antigen (OspB) as an active ingredient contains.
  • OspA Antibodies against the 31kD antigen
  • OspB Antibodies against the 34 kD Immunizing B.burgdorferi antigen
  • Subject matter of claim 1 for the contracting states AT, BE, CH / LI, DE, DK, FR, GB, IT, LU, NL and SE is an antigen that with an antigen against the 31 kD antigen (OspA) from B.burgdorferi immunoreacted and the amino acid sequence shown in Fig. 1 or contains an immunogenic epitope thereof.
  • object of claims 2 and 3 are preferred embodiments of this antigen.
  • the subject of claim 4 is a recombinant DNA molecule that is responsible for the aforementioned antigen encoded and the nucleic acid sequence shown in Fig. 1 or one of her in the context of the degeneration of the genetic Contains code corresponding sequence.
  • Subject of the claims 5 to 8 are recombinant vectors that contain one or more Contain copies of this recombinant DNA.
  • Subject of Claim 9 is a method for obtaining antigens from B.burgdorferi ZS7.
  • the subject of claims 10 to 12 is a active vaccine against Lyme disease.
  • a hybridoma cell line (deposited in the European Collection of Animal Cell Cultures on September 13, 1989, accession number ECACC 89 09 1302) which discloses an antibody LA-2 against OspA (IgG2b) produced. Furthermore, the antibody LA-26.1 against Hybridoma cell line producing OspA (IgG1) ECACC 90050406 (deposited on 4.05.1990), as well as the antibodies LA-25.1 or LA-27.1 against OspB (IgG2b or IgG1) producing Hybridoma cell lines ECACC 90050405 and ECACC 90050407 (deposited on 4.05.1990).
  • the pathogenic B.burgdorferi strain ZS7 is also disclosed (deposited in the German Collection of Microorganisms and Zellkulturen GmbH on September 19, 1989, accession number DSM5527).
  • An antigen that is associated with one of the called monoclonal antibodies immunoreacted.
  • Potentially immunogenic epitopes of these proteins can a specialist without difficulty through a structural analysis determine the OspA protein (e.g. Chou-Fassmann analysis) and then test their effectiveness experimentally.
  • a recombinant antigen which immunoreacts with one of the antibodies mentioned, where the DNA sequence coding for the antigen on a recombinant vector, preferably a prokaryotic Vector is located, which is suitable for protein expression.
  • An object of the invention is in particular an antigen from B. burgdorferi ZS7, specifically with the invention Antibodies immunoreacted and the in Fig. 1 amino acid sequence shown or an immunogenic epitope contains from this sequence.
  • the invention relates also a recombinant DNA which (1) the in Fig. 1 shown, (2) one, her in the context of degeneration nucleic acid sequence corresponding to the genetic code or (3) one with a sequence from (1) or / and (2) sequence hybridizing under stringent conditions contains that for the 31 kD antigen from B. burgdorferi ZS7 or an immunogenic epitope thereof.
  • stringent hybridization conditions is as in Maniatis et al., Molecular Cloning. A Laboratory Manual (1982), Cold Spring Harbor Laboratory, New York to understand.
  • An antigen according to the invention is particularly preferred which is a recombinant non-fusion protein or ⁇ -galactosidase fusion protein is.
  • the invention also includes a recombinant Vector containing one or more copies of an invention contains recombinant DNA.
  • the vector according to the invention can be a prokaryotic or / and eukaryotic vector, it is preferred a prokaryotic vector.
  • the recombinant Vector can be extrachromosomal in the host cell (e.g. plasmid) or it can also be located in the genome of the Integrate host cell (e.g. bacteriophage lambda).
  • the vector according to the invention is preferably a plasmid.
  • the recombinant vector is particularly preferred pZS-7 / 31-2 (DSM 5528).
  • the invention also relates to a method for Obtaining antigens according to the invention by examination a B. burgdorferi gene bank with one or several antibodies according to the invention, wherein the Clones isolated, which with the antibodies used show a positive immune response.
  • an antigen according to the invention is itself active Immunization, i.e. to induce antibody formation in the organism that can be used the invention thus also an active vaccine against Lyme disease, which is an active ingredient according to the invention Antigen, if necessary with usual carrier, Fillers and auxiliaries.
  • a preferred embodiment is when you have the antigen of the invention wins in a genetic engineering way.
  • mice of the strains CB-17 Scid (homozygous for the Scid mutation) and CB-17 were subcutaneously injected with 1x10 5 , 5x10 5 , 1x10 6 or 1x10 8 viable or killed (UV radiation) B. burgdorferi organisms in the tail root.
  • the detection of B. burgdorferi specific antibodies was carried out in a conventional ELISA procedure carried out (Justus et al., (1988) Wehrmed. Mschr. 32, 263).
  • the standard curve for the immunoglobulin content (Ig) was made by coating a bowl with anti-mouse Ig (1: 500 dilution of the serum solution from Paesel, Frankfurt, FRG) and titration of the total mouse IgG or IgM content (Calbiochem., LaJolla, USA). Total serum IgM and IgG were measured similarly.
  • the concentration of B. burgdorferi specific IgM or IgG antibodies is given in ⁇ g Ig / ml serum.
  • Table 1 shows that B. burgdorferi organisms of the isolates ZS7 and B31 during the entire test period in Blood from Scid mice that have previously been detected viable organisms have been vaccinated. Indeed could only use spirochetes from strain ZS7, but none from Strain B31 can be recultivated in vitro. By comparison of the recultivated organisms with the primary B. burgdorferi ZS7 isolate could not change the protein content or in the plasmid profile. No or only extremely low titers of irrelevant Antibodies were found in B. burgdorferi Scid mice throughout the observation period proven. In these animals none were made for B. burgdorferi specific IgM or IgG antibodies found (Table 1).
  • mice of the inbred strain BALB / c were homogenized with by sonication Borrelia (B. burgdorferi, strain B31; ATCC 35 210) immunized.
  • the immune spleen cells were identified using the Ag8-PAI myeloma cell line using standard methods using Polyethylene glycol fused (J.H. Peters, H. Baumgarten, M. Schulze “Monoclonal Antibodies” Springer-Verlag, Heidelberg).
  • the fusion products were seeded in 96 well tissue culture plates. After 8 days, the cell culture supernatants were examined for the presence of B. burgdorferi- specific monoclonal antibodies using a solid-phase ELISA (JH Peters et al., See above).
  • the hybridoma cells from antibody-producing cultures were cloned using the limit dilution method.
  • the culture supernatants from individual clones were then characterized again in the solid phase ELISA as well as by Western blot analysis and by immunofluorescence studies.
  • the monoclonal antibody LA-2 of the IgG2b subclass is produced and secreted by a monoclonal hybridoma line and reacts in a Western blot with the 31kDa structure (Osp-A) from all B. burgdorferi strains examined (including isolates ZS7 and B31 ) upon contact with B. burgdorferi proteins separated by electrophoresis on an SDS gel and transferred to a membrane by Western blot.
  • Osp-A 31kDa structure
  • LA-26.1C anti-ospA IgG1
  • LA 25.1 anti-OspB (34 kDa antigen)
  • IgG2b anti-OspB (34 kDa antigen)
  • LA 27.1 anti-OspB (34 kDa antigen)
  • mice were subcutaneously infected with 1x10 8 viable B. burgdorferi ZS7 organisms in the tail root.
  • the infected Scid mice were followed twice a week treated with different antisera. Which became a group with NMS (normal mouse serum), a second group with IMS (immune mouse serum) and a third group with the monoclonal Antibody LA-2 (against the 31 kD antigen of B. burgdorferi) treated.
  • the dose of administered Antisera was 100 ⁇ l or 100 ⁇ g in the first week with LA-2, in the second week 200 ⁇ l or 200 ⁇ g with LA-2 and in the third week 300 ⁇ l or 300 ⁇ g LA-2.
  • Table 2 shows that untreated or treated with NMS Scid mice clinical and histopathological after 12 days Signs of arthritis or carditis and Hepatitis developed. In contrast, the administration did of the LA-2 monoclonal antibody in Scid mice a significant reduction in symptoms. Were clinical only slight reddening of the joints and histopathologically only marginal changes. Treated with IMS Mice showed no clinical arthritis findings.
  • the B. burgdorferi pathogen could only be detected by in vitro cultivation in mice that were either untreated or treated with NMS. B. burgdorferi could not be detected in the mice treated with LA-2 or IMS (Table 2).
  • High molecular DNA from the B. burgdorferi strain ZS7 was after cultivation in modified Kelly's medium cleaned. The spirochetes were centrifuged Pelleted at 10,000 g and washed three times in PBS buffer. The dry pellet was dissolved in 10 ml TE (10 mmol / l Tris, 1 mmol / l EDTA, pH 7.4) resuspended, with lysozyme (5 mg / ml) treated at 30 ° C for 15 minutes and the DNA released by adding 1 ml of 20% SDS. After Adding 1.5 ml of NaCl (5 mol / l) was the solution with an equal volume of phenol extracted, followed by an extraction with chloroform.
  • the DNA was then by adding 2 volumes of absolute ethanol and incubation precipitated at -20 ° C overnight. After centrifugation the residue was dissolved in 0.5 ml TE and with DNAse free RNAse A (20 ⁇ g / ml) incubated at 55 ° C for 45 minutes, followed by a one hour treatment with Proteinase K (0.1 ⁇ g / ml) at 37 ° C. The solution was on 0.3 mol / l NaOAc adjusted and with phenol-chloroform extracted as described above. After precipitation with ethanol the DNA was resumed in TE.
  • coli (MC 1061) was the proportion of recombinant plaque-forming Units (pfu) determined as follows: random selected colonies were picked and saturated in 2 ml selection medium (LB with 25 ⁇ g / ml ampicillin) grown. The plasmid DNA was after the usual alkaline lysis method and then isolated cut with BamHI. More than 50% of the analyzed Plasmids contained an average of ⁇ 1.5 kb long DNA insertions.
  • the cells were plated on 24x24 cm plates at a density of 7,000 pfu per plate and incubated overnight at 30 ° C. After transferring the colonies to nitrocellulose filters (NC), the expression of ⁇ -galactosidase fusion proteins was induced by incubation at 42 ° C. for two hours. The filters were transferred to Whatman 3MM paper treated with 5% SDS and incubated at 95 ° C for about 25 minutes. The proteins were then electroblotted using conventional semi-dry western blotting equipment. After DNAse treatment of the NC filters, immunoreactive clones were identified by expression screening using monoclonal antibodies.
  • NC nitrocellulose filters
  • the inserted DNA of a recombinant E. coli clone with positive antibody reaction with LA-2 was on usual way isolated.
  • the DNA insertion of this clone contained the 31 kD antigen for the B. burgdorferi coding full length ospA gene.
  • the plasmid that containing the insertion was named pZS-7 / 31-2 and was awarded to DSM in accordance with the Budapest Treaty (under number DSM 5528) on September 19, 1989.
  • the recombinant produced by this immunopositive clone Protein was designated rZS7 / 31-2.
  • the coding DNA sequence of the ospA gene was determined. she is together with the derived amino acid sequence of the OspA protein shown in Fig. 1.
  • the recombinant proteins were then purified by affinity chromatography.
  • purified monoclonal antibodies LA-2 were covalently bound to activated Sepharose CL 4B.
  • the dialyzed urea extract with the recombinant protein was adsorbed on mouse IgG-Sepharose CL 4B and then passed over the LA-2-Sepharose CL 4B column.
  • the bound recombinant protein was eluted with 0.1 mol / l glycine / HCl - 0.1 mol / l NaCl, pH 2.5.
  • the pH of the collected fractions was neutralized by the immediate addition of 1/10 vol. 0.5 mol / l K 2 HPO 4 .
  • the protein-containing fractions were concentrated and dialyzed. The degree of purification was determined using SDS polyacrylamide gel electrophoresis.
  • the recombinant protein rZS7 / 31-2 became immunological examined.
  • the recombinant protein rB31 / 41-9 (B. burgdorferi 41 kD surface antigen) used.
  • the bound monoclonal antibodies were reacted with peroxidase-labeled species-specific anti-mouse immunoglobulins. Bound peroxidase-labeled antibodies were quantified using the orthophenylenediamine peroxidase substrate. The absorption at 492 nm (A 492 ) was determined directly in the microtiter plate using an automated plate photometer. The strength of the absorption is a measure of the amount of monoclonal antibodies bound.
  • the LA-2 monoclonal antibody is more specific Way with rZS7 / 31-2 but not with MC 1061 or rB31 / 41-9.
  • the control response of the monoclonal antibody LA-1 is specific for rB31 / 41-9.
  • the monoclonal Control antibody ACHT-2 (negative control) shows no significant reaction on any of the proteins.
  • Figure 2 shows that the monoclonal antibody LA-2 specifically recognized antigenic epitope the recombinant protein rZS7 / 31-2 is expressed, which was cloned from the genome of B. burgdorferi ZS7.
  • the monoclonal antibodies LA-2 and LA-26.1 the 31 kD antigen OspA and are of the isotype IgG2b or IgG1.
  • the monoclonal antibodies LA-25.1 and LA-27.1 recognize the 34 kD antigen OspB and are of the isotype IgG2b or IgG1.
  • the monoclonal antibodies LA-10 and LA-21 are specific for the flagella-associated 41 kD periplasmic protein from B. burgdorferi and are of the isotype IgG2a or IgG1. All of the above antibodies were according to the procedure described in Example 2 receive. It should be noted in this experiment whether monoclonal antibodies against another B. burgdorferi antigen in Scid mice a protection before the clinical symptoms of Lyme disease.
  • the polyclonal anti-B31 immune serum was taken from C57BL / 6 mice 91 days after subcutaneous inoculation with 1x10 8 B. burgdorferi B31 organisms.
  • the polyclonal anti-ZS7 IMS was removed from C57BL / 6 mice 68 days after subcutaneous inoculation with 1x10 8 B. burgdorferi ZS7. Both sera contained 60 ⁇ g / ml specific antibodies, as determined in an ELISA system (Schaible et al., J. Exp. Med. 170 (1989), 1427-1432).
  • the normal mouse serum (NMS) was taken from uninfected C57BL / 6 mice.
  • Scid mice using either Anti-ZS7IMS, Anti-B31IMS or treated with the monoclonal antibody LA-2 showed no visible clinical symptoms of Arthritis, i.e. there was no redness and swelling Tibial tarsal joints during the 21 days of observation on. Likewise, there were no symptoms of carditis and hepatitis ascertain. Histopathological examinations did not result in changes in the joints, the heart and the liver of Scid mice with either Anti-ZS7-IMS, Anti-B31-IMS or with the monoclonal Antibodies LA-2 have been treated.
  • the other OspA-specific monoclonal antibody LA-26.1 of the IgG1 isotype and the OspB specific Antibodies LA-25.1 and LA-27.1 were able to clinical symptoms of arthritis, carditis and hepatitis mitigate. Slight pathological signs were shown here Changes in the organs examined.
  • Scid mice given either PBS buffer, NMS or monoclonal antibodies to flagellin showed clinical signs of arthritis that showed pathological changes typical of untreated Scid mice (Table 3).
  • the severity of symptoms in the latter animals increased with time after inoculation and did not decrease during the entire observation period.
  • No spirochetes could be isolated from Scid mice that had previously been treated with either anti-ZS7IMS or the LA-2 antibody.
  • the detection of spirochetes by immunofluorescence and by cultivation from the blood of Scid mice was possible, using PBS buffer, NMS or the monoclonal antibodies LA-25.1, LA-26.1, LA-27.1, LA-10 or LA -21 had been treated.
  • mice with OspA happened as follows:
  • 3.2x10 10 spirochetes are for 2 hours at 4 ° C in 5 ml PBS / 7.5 ml n-butanol in the presence of protease inhibitors (5mmol / l EDTA, 5mmol / l benzamidine and 0.5mmol / l PMSF) on a magnetic stirrer touched. The mixture is then centrifuged for 90 minutes at 10,000 rpm and 4 ° C in the Sorvall centrifuge (fixed-angle rotor). The aqueous phase containing the surface proteins is removed and washed three times with chloroform.
  • protease inhibitors 5mmol / l EDTA, 5mmol / l benzamidine and 0.5mmol / l PMSF
  • the protein content is determined by the absorbance at 280 nm or determined with the BCA test.
  • C57BL6 or CB-17 mice were given 3 ⁇ at intervals of 7 to 10 days 5 ⁇ g (native OspA from strain B31) or 10 ⁇ g (native OspA from strain ZS7, recombinant OspA from ZS7) in 100 ⁇ l adjuvant (ABM3; Fa. Sebak, Aidenbach, FRG) given subcutaneously in the root of the tail. Serum could be withdrawn for 3 to 4 months at the earliest 3 weeks after the last immunization. The content of specific antibodies is determined in the ELISA system.

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EP94112143A 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit Expired - Lifetime EP0643974B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP98105444A EP0861664A3 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE3931236 1989-09-19
DE3931236 1989-09-19
DE4015911 1990-05-17
DE4015911A DE4015911A1 (de) 1989-09-19 1990-05-17 Impfstoff gegen die lyme-krankheit
EP90117943A EP0418827B1 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit

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EP90117943.2 Division 1990-09-18

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EP98105444A Division EP0861664A3 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit
EP98105444.8 Division-Into 1998-03-25

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EP0643974A1 EP0643974A1 (de) 1995-03-22
EP0643974B1 true EP0643974B1 (de) 1999-01-13

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EP94112143A Expired - Lifetime EP0643974B1 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit
EP90117943A Expired - Lifetime EP0418827B1 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit
EP94112144A Expired - Lifetime EP0633313B1 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit
EP94112145A Expired - Lifetime EP0633028B1 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit
EP98105444A Withdrawn EP0861664A3 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit

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EP90117943A Expired - Lifetime EP0418827B1 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit
EP94112144A Expired - Lifetime EP0633313B1 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit
EP94112145A Expired - Lifetime EP0633028B1 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit
EP98105444A Withdrawn EP0861664A3 (de) 1989-09-19 1990-09-18 Impfstoff gegen die Lyme-Krankheit

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US (6) US5178859A (cs)
EP (5) EP0643974B1 (cs)
JP (3) JP3205932B2 (cs)
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US7179448B2 (en) 1993-11-01 2007-02-20 Research Foundation Of The State Of New York Recombinant constructs of Borrelia burgdorferi
US7605248B2 (en) 1993-11-01 2009-10-20 Research Foundation Of The State University Of New York Recombinant constructs of Borrelia burgdorferi
US8680236B2 (en) 2000-08-18 2014-03-25 Brookhaven Sciences Associates, Llc Altered OspA of borrelia burgdorferi
US8992936B2 (en) 2000-08-18 2015-03-31 Research Foundation Of The State University Of New York Altered OspA of Borrelia burgdorferi

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US5178859A (en) 1993-01-12

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